Human Genome Project Provides High-Quality Sequences Needed for Study

BETHESDA, Md., June 18, 2003 - A detailed analysis of the just-completed sequence of the human Y chromosome - the chromosome that distinguishes males from females - has uncovered a novel mechanism by which it maintains its genetic integrity. The study is published in the current issue of Nature.

All other chromosomes occur in pairs and preserve genetic integrity by exchanging information with matching genes on the homologous chromosome, a process called "crossing over." But the Y chromosome lacks that option, being the only chromosome that is unpaired. Instead, the Y appears to exchange genes between the two copies of repeated sequences that lie near to each other as mirror images.

This phenomenon, called gene conversion - the non-reciprocal transfer of genetic information from one DNA molecule to another -- has been previously observed on a small scale over long evolutionary timescales between repeated sequences on the same chromosome, but not at the dramatic frequency apparently employed by the Y chromosome.

A research team, led by David C. Page, M.D., a Howard Hughes Medical Institute investigator at the Whitehead Institute for Biomedical Research in Cambridge, Mass.; Richard K. Wilson, Ph.D., director of the Genome Sequencing Center at Washington University School of Medicine in St. Louis; and Robert H. Waterston, M.D., Ph.D., formerly of Washington University's sequencing center and now at the University of Washington, Seattle, discovered that many of the sequences of chemical units -- called bases or base pairs -- that carry genetic information on the Y chromosome are arranged as palindromes. Palindromes are phrases or sentences that read the same backward or forward, such as "Madam, I'm Adam."

In the case of the Y, the palindromes are not just "junk" DNA; these strings of bases contain functioning genes important for male fertility. The team found that most of the sequence pairs are greater than 99.97 percent identical. The extensive use of gene conversion appears to play a role in the ability of the Y chromosome to edit out genetic mistakes and maintain the integrity of the relatively few genes it carries.

"This analysis of the Y chromosome could not have been done without the highly accurate sequence data produced by the Human Genome Project and made freely available to researchers everywhere in the world," said Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), which, along with the U.S. Department of Energy, led the Human Genome Project in the United States. "Unless the human sequence had been finished to the highest level of accuracy - less than one mistake in every 10,000 bases, the Y chromosome researchers would not have been able to identify the Y's unusual genetic structure and the novel mechanism for maintaining its integrity. Of all the human chromosomes, this was probably the most challenging to assemble correctly, and could never have been done without the painstaking map-based approach adopted by the International Human Genome Sequencing Consortium."

In a separate paper in the same issue of Nature, the team confirmed its findings by comparing similar regions of the Y chromosome in humans to the Y chromosomes of chimpanzees, bonobos (the pygmy chimpanzee) and gorillas. The comparison demonstrated that the same phenomenon of gene conversion appeared to be at work more than 5 million years ago, when humans and the non-human primates diverged from each other.

"The comparison between human and non-human primate chromosomes confirming the finding shows the power of comparative genomics," Dr. Collins said. "Without the ability to compare the genetic material across species, it would have been difficult for the team to test their hypothesis." NHGRI now funds a number of genome sequencing projects on model organisms, including the dog, the chimp, the chicken and the honeybee. The mouse, rat and fruit fly sequencing projects are essentially completed - except, ironically, for the Y chromosome of each of those species, which are still under construction.

The sequencing work on the Y chromosome was carried out at the Genome Sequencing Center at the Washington University School of Medicine as part of the Human Genome Project, which receives substantial funding from NHGRI. The Human Genome Project officially began in October 1990 and was completed in April 2003; sequencing the rough draft of the human genome sequence cost an estimated $300 million. The entire project, including genetic mapping, technology development, the study of model organisms, and the ethical, legal and social implications (ELSI) program was initially projected to take 15 years, but was completed more than two years early at a cost that was $400 million less than expected.

The initial analysis of the draft human genome sequence was published in February 2001. With the completion of the project, researchers plan to publish a separate analysis on each completed chromosome over the next year or so.

NHGRI is one of the 27 institutes and centers at the National Institutes of Health, an agency of the Department of Health and Human Services. Additional information about NHGRI can be found at its Web site, www.genome.gov.